Submissions for variant NM_000051.4(ATM):c.7445T>C (p.Met2482Thr)

dbSNP: rs1555123191

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553049	SCV000622749	uncertain significance	Ataxia-telangiectasia syndrome	2023-03-30	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 453685). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with ATM-related conditions (PMID: 35047863). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2482 of the ATM protein (p.Met2482Thr).
Ambry Genetics	RCV000562572	SCV000672634	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-25	criteria provided, single submitter	clinical testing	The p.M2482T variant (also known as c.7445T>C), located in coding exon 49 of the ATM gene, results from a T to C substitution at nucleotide position 7445. The methionine at codon 2482 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779799	SCV000916603	uncertain significance	not specified	2018-10-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7445T>C (p.Met2482Thr) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246004 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7445T>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003148773	SCV003837361	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176, 35047863)
Baylor Genetics	RCV003470685	SCV004212143	uncertain significance	Familial cancer of breast	2022-12-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000553049	SCV001452134	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-24	no assertion criteria provided	clinical testing